Taxol was first isolated from the stem bark of Western Yew, Taxus brevifolia Nutt (Taxaceae) and has the following structure (with the 2'-, 7-, 10- and 13th-positions indicated) ##STR2## In ongoing clinical trials sponsored by the National Cancer Institute (NCI), taxol has shown promising results in fighting advanced cases of ovarian, breast, and other cancers.
Taxol is unique among antimitotic drugs in that it promotes the assembly of stable microtubules from tubulin even under otherwise unfavorable conditions. The drug binds to microtubules, stabilizing them from depolymerization, thus disrupting the tubulin-microtubule equilibrium and consequently inhibiting mitosis. The mechanism of action, toxicology, clinical efficacy, etc. of taxol are reviewed in a number of articles, such as in an article by Rowinsky et al. in Taxol: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: p 1247 (1990).
Since the discovery of significant effectiveness in cancer treatment, many laboratories have launched to design taxol analogues in search of better pharmacological profiles. Out of such program was the discovery of taxotere of the formula ##STR3## which has been reported to be as effective as taxol at promoting the assembly of microtubules and approximately twice as cytotoxic. See, Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substitutents and Variable C-2' Configurations, J. Med. Chem., 34, p 1176 (1991); Relationships between the Structure of Taxol Analogues and Their Antimitotic Activity, J. Med. Chem., 34, p 992 (1991).
In recent years, the introduction of fluorine into pharmacologically active compounds has led to the discovery of some profound and unexpected results. (For a comprehesive review on the advances in the preparation of biologically active organofluorine compounds, see: Advances in the Preparation of Biologically Active Organofluorine Compounds, Tetrahedron, 43, No. 14, p 3123 (1987).) It is the intention of the present invention to provide fluorinated taxols and their derivatives.